极光激酶A抑制在arid1a突变的胃肠胰神经内分泌癌中作为一种合成致死策略。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-09-16 DOI:10.1016/j.canlet.2025.218033

Maria Urbanova , Fabrice Viol , Laura Ruiz-Cañas , Efthymios Koniaris , Rihards Saksis , Sandra Batres-Ramos , Julie Earl , Agapi Kataki , Verona Buocikova , Monika Burikova , Marina Cihova , Lucia Rojikova , Peter Makovicky , Miroslava Matuskova , Yvonne Kohl , Andrea Riedmayer , Marianna Makova , Ladislav Baciak , Daniel Gogola , Olesja Rogoza , Joerg Schrader

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引用次数: 0

摘要

顺铂（CDDP）和依托泊苷（ETO）化疗是胃肠胰神经内分泌癌（GEP-NEC）的标准治疗方法。尽管初始反应率很高，但治疗相关的毒性和获得性耐药仍然是重大的临床挑战。目前尚无针对这种侵袭性癌症的分子靶向治疗方法。在这里，我们评估了alisertib （ALI）作为arid1a缺陷的GEP-NEC的合成致死策略的极光激酶抑制作用。采用gep - nec来源的NT-38细胞系建立免疫缺陷小鼠皮下和原位异种移植模型，比较ALI与CDDP+ETO的治疗效果。通过免疫组织化学、Western blotting和RNA测序评估肿瘤反应。为了证实ARID1A依赖性，我们在胰腺神经内分泌NT-18LM细胞系中诱导了短暂敲低，表明ALI敏感性在ARID1A缺陷细胞中显著增强。ALI达到了与化疗相当的抗肿瘤疗效，并且耐受性良好，相对于CDDP+ETO，体重减轻最小。远处转移是GEP-NEC的早期特征，在6周内在5只动物中发生，其中2只接受ALI治疗，3只接受对照。转录组学分析显示，这两种处理在信号转导、局灶黏附、受体酪氨酸激酶和VEGFA-VEGFR2信号传导方面具有收敛性，而ALI独特地富集了与胰腺分泌、脂质代谢、内质网蛋白加工和细胞外基质组织相关的途径。这些发现表明，极光激酶抑制在arid1a缺陷的GEP-NEC中具有不同的机制和选择性效果。鉴于其疗效、良好的耐受性和arid1a依赖性特异性，ALI可能是铂基化疗的一个有希望的替代方案，为进一步开发机制驱动的GEP-NEC联合治疗策略提供了强有力的理论依据。

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Aurora kinase A inhibition as a synthetic lethality strategy in ARID1A-mutated gastroenteropancreatic neuroendocrine carcinoma

Chemotherapy with cisplatin (CDDP) and etoposide (ETO) is the standard treatment for gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Despite high initial response rates, treatment-related toxicity and acquired resistance remain significant clinical challenges. No molecularly targeted therapies are currently established for this aggressive cancer. Here, we evaluated Aurora kinase inhibition with alisertib (ALI) as a synthetic lethality strategy in ARID1A-deficient GEP-NEC. Subcutaneous and orthotopic xenograft models were established in immunodeficient mice using the GEP-NEC-derived NT-38 cell line, and the therapeutic efficacy of ALI was compared with CDDP + ETO. Tumor responses were assessed by immunohistochemistry, Western blotting, and RNA sequencing. To confirm ARID1A dependency, transient knockdown was induced in the pancreatic neuroendocrine NT-18LM cell line, demonstrating that ALI sensitivity is significantly enhanced in ARID1A-deficient cells. ALI achieved antitumor efficacy comparable to chemotherapy and was well tolerated, with minimal weight loss relative to CDDP + ETO. Distant metastases, an early feature of GEP-NEC, developed in five animals over six weeks, two of which were treated with ALI and three controls. Transcriptomic profiling revealed convergence of both treatments on signal transduction, focal adhesion, receptor tyrosine kinase, and VEGFA-VEGFR2 signaling, while ALI uniquely enriched pathways related to pancreatic secretion, lipid metabolism, protein processing in the endoplasmic reticulum, and extracellular matrix organization. These findings establish Aurora kinase inhibition as mechanistically distinct and selectively effective in ARID1A-deficient GEP-NEC. Given its efficacy, favorable tolerability, and ARID1A-dependent specificity, ALI may represent a promising alternative to platinum-based chemotherapy, offering a strong rationale for further development of mechanism-driven combination strategies for GEP-NEC.

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.